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Linearolactone Induces Necrotic-like Death in Giardia intestinalis Trophozoites: Prediction of a Likely Target

Linearolactone (LL) is a neo-clerodane type diterpene that has been shown to exert giardicidal effects; however, its mechanism of action is unknown. This work analyzes the cytotoxic effect of LL on Giardia intestinalis trophozoites and identifies proteins that could be targeted by this active natura...

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Autores principales: Argüello-García, Raúl, Calzada, Fernando, Chávez-Munguía, Bibiana, Matus-Meza, Audifás-Salvador, Bautista, Elihú, Barbosa, Elizabeth, Velazquez, Claudia, Hernández-Caballero, Marta Elena, Ordoñez-Razo, Rosa Maria, Velázquez-Domínguez, José Antonio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9324340/
https://www.ncbi.nlm.nih.gov/pubmed/35890108
http://dx.doi.org/10.3390/ph15070809
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author Argüello-García, Raúl
Calzada, Fernando
Chávez-Munguía, Bibiana
Matus-Meza, Audifás-Salvador
Bautista, Elihú
Barbosa, Elizabeth
Velazquez, Claudia
Hernández-Caballero, Marta Elena
Ordoñez-Razo, Rosa Maria
Velázquez-Domínguez, José Antonio
author_facet Argüello-García, Raúl
Calzada, Fernando
Chávez-Munguía, Bibiana
Matus-Meza, Audifás-Salvador
Bautista, Elihú
Barbosa, Elizabeth
Velazquez, Claudia
Hernández-Caballero, Marta Elena
Ordoñez-Razo, Rosa Maria
Velázquez-Domínguez, José Antonio
author_sort Argüello-García, Raúl
collection PubMed
description Linearolactone (LL) is a neo-clerodane type diterpene that has been shown to exert giardicidal effects; however, its mechanism of action is unknown. This work analyzes the cytotoxic effect of LL on Giardia intestinalis trophozoites and identifies proteins that could be targeted by this active natural product. Increasing concentrations of LL and albendazole (ABZ) were used as test and reference drugs, respectively. Cell cycle progression, determination of reactive oxygen species (ROS) and apoptosis/necrosis events were evaluated by flow cytometry (FCM). Ultrastructural alterations were analyzed by transmission electron microscopy (TEM). Ligand–protein docking analyses were carried out using the LL structure raised from a drug library and the crystal structure of an aldose reductase homologue (GdAldRed) from G. intestinalis. LL induced partial arrest at the S phase of trophozoite cell cycle without evidence of ROS production. LL induced pronecrotic death in addition to inducing ultrastructural alterations as changes in vacuole abundances, appearance of perinuclear and periplasmic spaces, and deposition of glycogen granules. On the other hand, the in silico study predicted that GdAldRed is a likely target of LL because it showed a favored change in Gibbs free energy for this complex.
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spelling pubmed-93243402022-07-27 Linearolactone Induces Necrotic-like Death in Giardia intestinalis Trophozoites: Prediction of a Likely Target Argüello-García, Raúl Calzada, Fernando Chávez-Munguía, Bibiana Matus-Meza, Audifás-Salvador Bautista, Elihú Barbosa, Elizabeth Velazquez, Claudia Hernández-Caballero, Marta Elena Ordoñez-Razo, Rosa Maria Velázquez-Domínguez, José Antonio Pharmaceuticals (Basel) Article Linearolactone (LL) is a neo-clerodane type diterpene that has been shown to exert giardicidal effects; however, its mechanism of action is unknown. This work analyzes the cytotoxic effect of LL on Giardia intestinalis trophozoites and identifies proteins that could be targeted by this active natural product. Increasing concentrations of LL and albendazole (ABZ) were used as test and reference drugs, respectively. Cell cycle progression, determination of reactive oxygen species (ROS) and apoptosis/necrosis events were evaluated by flow cytometry (FCM). Ultrastructural alterations were analyzed by transmission electron microscopy (TEM). Ligand–protein docking analyses were carried out using the LL structure raised from a drug library and the crystal structure of an aldose reductase homologue (GdAldRed) from G. intestinalis. LL induced partial arrest at the S phase of trophozoite cell cycle without evidence of ROS production. LL induced pronecrotic death in addition to inducing ultrastructural alterations as changes in vacuole abundances, appearance of perinuclear and periplasmic spaces, and deposition of glycogen granules. On the other hand, the in silico study predicted that GdAldRed is a likely target of LL because it showed a favored change in Gibbs free energy for this complex. MDPI 2022-06-29 /pmc/articles/PMC9324340/ /pubmed/35890108 http://dx.doi.org/10.3390/ph15070809 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Argüello-García, Raúl
Calzada, Fernando
Chávez-Munguía, Bibiana
Matus-Meza, Audifás-Salvador
Bautista, Elihú
Barbosa, Elizabeth
Velazquez, Claudia
Hernández-Caballero, Marta Elena
Ordoñez-Razo, Rosa Maria
Velázquez-Domínguez, José Antonio
Linearolactone Induces Necrotic-like Death in Giardia intestinalis Trophozoites: Prediction of a Likely Target
title Linearolactone Induces Necrotic-like Death in Giardia intestinalis Trophozoites: Prediction of a Likely Target
title_full Linearolactone Induces Necrotic-like Death in Giardia intestinalis Trophozoites: Prediction of a Likely Target
title_fullStr Linearolactone Induces Necrotic-like Death in Giardia intestinalis Trophozoites: Prediction of a Likely Target
title_full_unstemmed Linearolactone Induces Necrotic-like Death in Giardia intestinalis Trophozoites: Prediction of a Likely Target
title_short Linearolactone Induces Necrotic-like Death in Giardia intestinalis Trophozoites: Prediction of a Likely Target
title_sort linearolactone induces necrotic-like death in giardia intestinalis trophozoites: prediction of a likely target
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9324340/
https://www.ncbi.nlm.nih.gov/pubmed/35890108
http://dx.doi.org/10.3390/ph15070809
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